Cdc25 (p80cdc25, M-phase inducer phosphatase) is the protein tyrosine phosphatase that triggers entry into mitosis in fission yeast. It dephosphorylates the cyclin-dependent kinase Cdc2 (CDK1) on the inhibitory residue Tyr15, thereby activating the Cdc2-cyclin B (Cdc13) kinase; this Tyr15 dephosphorylation is the rate-limiting step for the G2/M transition. Cdc25 is the positive counterpart of the inhibitory Wee1/Mik1 tyrosine kinases, and it acts as a dosage-dependent mitotic inducer: increasing Cdc25 concentration as cells grow couples cell size to the timing of division. Catalysis uses a rhodanese-fold catalytic domain with an essential active-site cysteine (Cys480) that forms a phosphocysteine intermediate. Cdc25 is the principal target through which the DNA replication and DNA damage checkpoints, and the stress-activated Sty1/Srk1 pathway, restrain mitotic entry: the checkpoint kinases Chk1, Cds1 and Srk1 phosphorylate Cdc25, creating 14-3-3 (Rad24/Rad25) binding sites that promote its nuclear exclusion and inhibit its ability to activate Cdc2. Cdc25 shuttles between cytoplasm and nucleus, with nuclear accumulation highest in G2. The same Cdc2-Tyr15 dephosphorylating activity is also required for meiotic nuclear divisions, where cdc25 expression is driven by the meiotic transcription factor Mei4.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Cdc25 is partly nuclear; it shuttles between cytoplasm and nucleus, with nuclear accumulation highest in G2 where it must access its substrate Cdc2. Nuclear localization is supported by direct S. pombe experimental data. Reason: Phylogenetic inference is consistent with direct S. pombe localization data showing Cdc25 in both nucleus and cytoplasm. Supporting Evidence: PMID:10523629 wild-type Cdc25, which localized to both the cytoplasm and the nucleus. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cdc25 is present in the cytoplasm as well as the nucleus; checkpoint and stress signaling drive 14-3-3-dependent cytoplasmic accumulation to sequester Cdc25 away from its nuclear substrate. Reason: Supported by phylogenetic inference and corroborated by direct S. pombe localization data. Supporting Evidence: PMID:15629716 Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein family member, and accumulation of Cdc25 in the cytoplasm. |
| GO:0000086 G2/M transition of mitotic cell cycle | IBA GO_REF:0000033 | ACCEPT | Summary: Cdc25 acts at the G2/M transition by dephosphorylating Cdc2-Tyr15 to trigger mitotic entry. This is a core process, though the directional term positive regulation of G2/M transition (GO:0010971) more precisely captures Cdc25's activating role. Reason: Cdc25 is the founding mitotic inducer acting at G2/M; well supported by classical genetics. Supporting Evidence: PMID:3955656 the cdc25+ gene function is required to initiate |
| GO:0010971 positive regulation of G2/M transition of mitotic cell cycle | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. Cdc25 is a dosage-dependent positive regulator of mitotic entry: increased Cdc25 advances mitosis to a smaller cell size, and it counteracts the inhibitory Wee1 kinase. Reason: This is the central, experimentally established role of Cdc25 as the mitotic inducer counteracting Wee1. Supporting Evidence: PMID:3955656 increased cdc25+ expression causes mitosis to initiate at a reduced cell size. This shows that cdc25+ functions as a dosage-dependent inducer in mitotic control |
| GO:0110032 positive regulation of G2/MI transition of meiotic cell cycle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cdc25 also drives the meiotic G2/MI transition using the same Cdc2-Tyr15 dephosphorylation; its expression in meiosis is induced by Mei4. This is a genuine but non-core role relative to its central mitotic function. Reason: Meiotic involvement is experimentally supported (not an SPKW keyword artifact), but it is a deployment of the same activity in meiosis rather than the primary mitotic function. Supporting Evidence: PMID:17804800 Forced dephosphorylation of Cdc2p on tyrosine-15 thus induced meiosis I in mei4 mutant cells without a delay |
| GO:0004725 protein tyrosine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function. Cdc25 is a protein tyrosine phosphatase (EC 3.1.3.48) that dephosphorylates Cdc2-Tyr15; the IEA mapping is fully consistent with direct experimental evidence. Reason: Strongly supported by direct biochemical and genetic data demonstrating tyrosine phosphatase activity toward Cdc2. Supporting Evidence: PMID:1756737 GST-cdc25) caused tyrosyl dephosphorylation and activation of immunoprecipitated p34cdc2 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization mapped from UniProt Subcellular Location vocabulary; consistent with direct S. pombe data showing Cdc25 accumulates in the nucleus, highest in G2. Reason: Concordant with experimental localization evidence. Supporting Evidence: PMID:10523629 wild-type Cdc25, which localized to both the cytoplasm and the nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization mapped from UniProt Subcellular Location vocabulary; consistent with the experimentally observed cytoplasm/nucleus distribution and 14-3-3-driven cytoplasmic sequestration. Reason: Concordant with experimental localization evidence. Supporting Evidence: PMID:10523629 wild-type Cdc25, which localized to both the cytoplasm and the nucleus. |
| GO:1902751 positive regulation of cell cycle G2/M phase transition | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO term that is essentially equivalent to GO:0010971 (positive regulation of G2/M transition of mitotic cell cycle), which is more specific and already directly supported. Redundant with the mitotic-specific term. Reason: The mitotic-specific child term GO:0010971 is preferred over this more general cell cycle phase transition term. Proposed replacements: positive regulation of G2/M transition of mitotic cell cycle Supporting Evidence: PMID:3955656 cdc25+ functions as a dosage-dependent inducer in mitotic control |
| GO:0004725 protein tyrosine phosphatase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of protein tyrosine phosphatase activity; redundant with the strong direct IDA evidence in S. pombe but correct. Reason: Correct function, directly demonstrated experimentally in S. pombe. Supporting Evidence: PMID:1756737 cdc25 proteins directly dephosphorylate and activate p34cdc2 kinase to induce M-phase |
| GO:0031569 mitotic G2 cell size control checkpoint signaling | IMP PMID:28479325 Size-Dependent Expression of the Mitotic Activator Cdc25 Sug... | ACCEPT | Summary: Size-dependent expression of Cdc25 provides a cell-size control mechanism: smaller cells make less Cdc25 and larger cells more, so cells trigger division when Cdc25 reaches a threshold concentration. A bona fide core-related role in coupling cell size to mitotic entry. Reason: Directly supported by the cited study demonstrating size-dependent Cdc25 expression as a size-control mechanism. Supporting Evidence: PMID:28479325 cdc25 transcript levels are regulated such that smaller cells express less Cdc25 and larger cells express more Cdc25, creating an increasing concentration of Cdc25 as cells grow and providing a mechanism for cells to trigger cell division when they reach a threshold concentration of Cdc25 |
| GO:0004725 protein tyrosine phosphatase activity | IMP PMID:9042863 Cdc2 tyrosine phosphorylation is required for the DNA damage... | ACCEPT | Summary: This paper shows the DNA damage checkpoint G2 arrest depends on inhibitory Cdc2-Tyr15 phosphorylation and that the rate of Cdc2 tyrosine dephosphorylation (mainly via Cdc25) is reduced by irradiation. It supports Cdc25 acting as the Cdc2 tyrosine dephosphorylating activity in the checkpoint context but is not a direct enzymatic assay of Cdc25 PTP activity. The molecular function itself is better and more directly supported by IDA references. Reason: Function is correct (Cdc25 is the Cdc2 tyrosine phosphatase) and the cited work is consistent, though this is genetic/indirect; stronger IDA evidence exists. Supporting Evidence: PMID:9042863 the rate of Cdc2 tyrosine dephosphorylation is reduced by irradiation. This result implicates regulation of Cdc2 tyrosine dephosphorylation, mainly carried out by the Cdc25 tyrosine phosphatase |
| GO:0110044 regulation of cell cycle switching, mitotic to meiotic cell cycle | IMP PMID:17804800 Mei4p coordinates the onset of meiosis I by regulating cdc25... | KEEP AS NON CORE | Summary: cdc25 is a key Mei4 target controlling entry into meiosis I; forced Cdc2-Tyr15 dephosphorylation bypasses the mei4 arrest. Cdc25 thus contributes to the transition into the meiotic program. A genuine non-core meiotic role. Reason: Experimentally supported meiotic involvement, but secondary to the core mitotic function. Supporting Evidence: PMID:17804800 cdc25+ is an important target of Mei4p in control of entry into meiosis I |
| GO:0004721 phosphoprotein phosphatase activity | IDA PMID:22665807 Multisite phosphoregulation of Cdc25 activity refines the mi... | MODIFY | Summary: Broad parent term for phosphatase activity. Cdc25 is specifically a protein tyrosine phosphatase (GO:0004725); the more specific term should be used. The cited paper concerns Cdk1/Clp1 phosphoregulation of Cdc25 catalytic activation rather than a new substrate specificity. Reason: The specific tyrosine phosphatase term is more informative than the general phosphoprotein phosphatase activity term. Proposed replacements: protein tyrosine phosphatase activity Supporting Evidence: PMID:22665807 Cdc25 hyperphosphorylation by Cdk1 governs Cdc25 catalytic activation |
| GO:0005634 nucleus | IDA PMID:18272791 Activation of Srk1 by the mitogen-activated protein kinase S... | ACCEPT | Summary: Direct S. pombe evidence; Srk1 negatively regulates the cycle by inhibiting Cdc25 and driving its nucleus-to-cytoplasm relocation, consistent with a nuclear pool of Cdc25 acting on Cdc2. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:18272791 activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25 |
| GO:0005829 cytosol | IDA PMID:18272791 Activation of Srk1 by the mitogen-activated protein kinase S... | ACCEPT | Summary: Cytosolic pool of Cdc25 consistent with Srk1/14-3-3-dependent cytoplasmic sequestration. Direct S. pombe evidence. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:18272791 activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25 |
| GO:0004725 protein tyrosine phosphatase activity | IDA PMID:1703321 Complementation of the mitotic activator, p80cdc25, by a hum... | ACCEPT | Summary: Direct demonstration that Tyr15 dephosphorylation activates the Cdc2-cyclin complex and that a human PTPase substitutes for p80cdc25, reinforcing the tyrosine phosphatase identity of Cdc25. Core molecular function. Reason: Direct evidence for tyrosine phosphatase activity in the Cdc2 activation pathway. Supporting Evidence: PMID:1703321 dephosphorylation of Tyr15 triggered activation of the pp34-cyclin complex from fission yeast, that a human protein-tyrosine phosphatase can catalyze this event both in vitro and in vivo |
| GO:0010971 positive regulation of G2/M transition of mitotic cell cycle | IMP PMID:1703321 Complementation of the mitotic activator, p80cdc25, by a hum... | ACCEPT | Summary: Cdc25 (and the complementing human PTPase) positively regulates mitotic entry via Cdc2-Tyr15 dephosphorylation. Core process, well supported. Reason: Directly supports Cdc25's positive role in the G2/M transition. Supporting Evidence: PMID:1703321 The complementary DNA that encoded the tyrosine phosphatase replaced the mitotic activator p80cdc25, closely associating the cdc25(+)-activating pathway with tyrosine dephosphorylation of pp34. |
| GO:0072435 response to mitotic G2 DNA damage checkpoint signaling | IMP PMID:9278510 Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint... | ACCEPT | Summary: Cdc25 is the direct target of the Chk1 DNA damage checkpoint kinase (and not Wee1); Chk1 associates with and phosphorylates Cdc25 to restrain mitosis after damage. Core checkpoint-related function as the regulated node. Reason: Strong genetic and biochemical evidence that Cdc25 is the effector target of the G2 DNA damage checkpoint. Supporting Evidence: PMID:9278510 These findings identify Cdc25, but not Wee1, as a target of the DNA damage checkpoint |
| GO:0005515 protein binding | IPI PMID:9278510 Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint... | MARK AS OVER ANNOTATED | Summary: Bare protein binding referring to the Cdc25-Chk1 interaction (Chk1 is the checkpoint kinase acting on Cdc25). Uninformative as a molecular function; the functional content is captured by the DNA damage checkpoint BP term. Reason: Per curation guidelines, bare protein binding is uninformative; the relevant biology (Cdc25 as a Chk1 substrate/target) is better represented by checkpoint process terms. Supporting Evidence: PMID:9278510 Cdc25 associated with Chk1 in vivo and was phosphorylated when copurified in Chk1 complexes |
| GO:0005515 protein binding | IPI PMID:9774107 Replication checkpoint requires phosphorylation of the phosp... | MODIFY | Summary: Bare protein binding covering the Cds1/Chk1 and Rad24 (14-3-3) interactions. The 14-3-3 interaction is functionally important and is better represented by the specific term 14-3-3 protein binding (GO:0071889). Reason: Replace uninformative protein binding with the specific 14-3-3 protein binding term that captures the checkpoint-relevant interaction with Rad24. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:9774107 Phosphorylation of Cdc25 promotes its binding to 14-3-3 proteins, preventing it from activating Cdc2 |
| GO:0005515 protein binding | IPI PMID:10523629 DNA damage and replication checkpoints in fission yeast requ... | MODIFY | Summary: Bare protein binding referring to the Cdc25-Rad24 (14-3-3) interaction that mediates checkpoint-dependent nuclear exclusion. The specific term 14-3-3 protein binding is more informative. Reason: Replace uninformative protein binding with 14-3-3 protein binding, capturing the functionally characterized Rad24 interaction. Proposed replacements: 14-3-3 protein binding Supporting Evidence: PMID:10523629 Nuclear exclusion of wild-type Cdc25 was observed upon overproduction of Rad 24, one of the two fission yeast 14-3-3 proteins |
| GO:0110032 positive regulation of G2/MI transition of meiotic cell cycle | IMP PMID:25492408 Meiotic nuclear movements in fission yeast are regulated by ... | KEEP AS NON CORE | Summary: Cdc25 triggers entry into meiotic nuclear divisions by activating CDK, downstream of the replication checkpoint and independently of Mei4 once expressed. A real non-core meiotic role using the core Cdc2-activating activity. Reason: Experimentally supported meiotic role, secondary to the core mitotic function. Supporting Evidence: PMID:25492408 Mei4 is also required for the expression of phosphatase Cdc25, which activates cyclin-dependent kinase (CDK), and is thereby essential for triggering meiotic nuclear divisions |
| GO:0004725 protein tyrosine phosphatase activity | IDA PMID:1464318 Pyp3 PTPase acts as a mitotic inducer in fission yeast. | ACCEPT | Summary: This paper characterizes Pyp3 as a second PTPase that cooperates with p80cdc25 to dephosphorylate Cdc2-Tyr15; it confirms cdc25 is a protein tyrosine phosphatase but the direct enzymatic data are on Pyp3, not Cdc25. The MF assignment to Cdc25 is correct but more directly supported by other references. Reason: Function is correct (Cdc25 is the major Cdc2 PTPase); strongest direct evidence is in other references. Supporting Evidence: PMID:1464318 the actions of the p107wee1 tyrosine kinase and p80cdc25 protein tyrosine phosphatase (PTPase) |
| GO:0005515 protein binding | IPI PMID:11812792 Solution NMR study of the monomeric form of p13suc1 protein ... | MARK AS OVER ANNOTATED | Summary: Bare protein binding linked to an NMR structural study of p13suc1/CKS. The paper is about Suc1 structure and does not substantively characterize a functional Cdc25-Suc1 interaction; uninformative and peripheral for Cdc25. Reason: Bare protein binding is uninformative, and the cited reference is a Suc1 structural study rather than a characterization of a Cdc25 interaction. Supporting Evidence: PMID:11812792 Cyclin-dependent kinase subunit (CKS) proteins bind to cyclin-dependent kinases and target various proteins to phosphorylation and proteolysis during cell division |
| GO:0005634 nucleus | IDA PMID:15629716 Inactivation of the Cdc25 phosphatase by the stress-activate... | ACCEPT | Summary: Direct S. pombe evidence that Cdc25 localizes to the nucleus (and cytoplasm), with Srk1/14-3-3 controlling its compartmentalization. Nuclear pool is where Cdc25 activates Cdc2. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:15629716 Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein family member, and accumulation of Cdc25 in the cytoplasm. |
| GO:0005737 cytoplasm | IDA PMID:15629716 Inactivation of the Cdc25 phosphatase by the stress-activate... | ACCEPT | Summary: Direct S. pombe evidence for a cytoplasmic pool of Cdc25, increased upon Srk1 phosphorylation and 14-3-3 (Rad24) binding. Reason: Supported by direct experimental localization in S. pombe. Supporting Evidence: PMID:15629716 Phosphorylation by Srk1 causes Cdc25 to bind to Rad24, a 14-3-3 protein family member, and accumulation of Cdc25 in the cytoplasm. |
| GO:0031573 mitotic intra-S DNA damage checkpoint signaling | IMP PMID:15297457 On the slowing of S phase in response to DNA damage in fissi... | ACCEPT | Summary: The intra-S DNA damage checkpoint (Rad3-Cds1 pathway) acts on Cdc2, with Cdc25 regulation contributing to S-phase slowing. Cdc25 participates as the regulated Cdc2 activator. Keep as a checkpoint-related role. Reason: Cdc25 is part of the intra-S checkpoint response acting through Cdc2 regulation. Supporting Evidence: PMID:15297457 a major downstream target of this pathway is the cyclin-dependent kinase, Cdc2 |
| GO:0010971 positive regulation of G2/M transition of mitotic cell cycle | IMP PMID:2665944 Regulation of p34cdc2 protein kinase during mitosis. | ACCEPT | Summary: The cdc25+ gene product activates the p34cdc2 protein kinase to initiate mitosis, the canonical positive regulation of the G2/M transition. Core process. Reason: Directly supports Cdc25's positive role in mitotic initiation. Supporting Evidence: PMID:2665944 the cdc25+ gene product activating the p34cdc2 protein kinase leading to mitotic initiation |
| GO:0004725 protein tyrosine phosphatase activity | IDA PMID:1756737 p80cdc25 mitotic inducer is the tyrosine phosphatase that ac... | ACCEPT | Summary: Definitive demonstration that p80cdc25 is the tyrosine phosphatase that dephosphorylates and activates p34cdc2, with active-site Cys480 essential. Core molecular function with the strongest direct evidence. Reason: Direct biochemical evidence (tyrosyl dephosphorylation, PTPase properties, catalytic cysteine mutation) for Cdc25 PTP activity. Supporting Evidence: PMID:1756737 Mutation of the cdc25 Cys480 codon, corresponding to an essential cysteine in the active site of PTPases, abolished the phosphatase activity of GST-cdc25 |
| GO:0005829 cytosol | HDA PMID:16823372 ORFeome cloning and global analysis of protein localization ... | ACCEPT | Summary: High-throughput YFP-based localization places Cdc25 in the cytosol, consistent with its known cytoplasmic/nuclear shuttling. Lower-resolution evidence but concordant with focused studies. Reason: Genome-wide localization data consistent with the experimentally established cytoplasm/nucleus distribution. Supporting Evidence: PMID:15629716 accumulation of Cdc25 in the cytoplasm. |
| GO:0008361 regulation of cell size | NAS GO_REF:0000051 | MODIFY | Summary: Cdc25 regulates the cell size at which division occurs (dosage-dependent mitotic inducer; size-dependent expression). The more specific term mitotic G2 cell size control checkpoint signaling (GO:0031569), already annotated with IMP, better captures the mechanism. Reason: A more specific, experimentally supported size-control checkpoint term is available; replace the general cell-size term. Proposed replacements: mitotic G2 cell size control checkpoint signaling Supporting Evidence: PMID:28479325 smaller cells express less Cdc25 and larger cells express more Cdc25 |
| GO:0004725 protein tyrosine phosphatase activity | IDA PMID:1819507 cdc25 M-phase inducer. | ACCEPT | Summary: p80cdc25 directly dephosphorylates Tyr-15 of p34cdc2; supports the core tyrosine phosphatase activity. Concordant with other direct evidence. Reason: Direct evidence for Cdc25-mediated Cdc2-Tyr15 dephosphorylation. Supporting Evidence: PMID:1819507 p80cdc25 encodes a phosphate that acts by directly dephosphorylating the Tyr-15 residue of p34cdc2 |
| GO:0005634 nucleus | IDA PMID:1500423 cdc25 is a nuclear protein expressed constitutively througho... | ACCEPT | Summary: This study characterizes the MAMMALIAN cdc25 protein in nontransformed fibroblasts (nuclear during interphase), not the S. pombe protein. The localization is therefore heterologous/orthology-based support rather than direct S. pombe evidence, but it is consistent with the native nuclear pool. Reason: Nuclear localization is consistent with direct S. pombe data; however the cited reference is mammalian, so it provides only orthologous (ISS-like) support. Supporting Evidence: PMID:1500423 cdc25 protein is found essentially localized in the nucleus throughout interphase and during early prophase |
| GO:0005737 cytoplasm | IDA PMID:1500423 cdc25 is a nuclear protein expressed constitutively througho... | ACCEPT | Summary: Mammalian cdc25 redistributes to the cytoplasm around nuclear envelope breakdown in fibroblasts; this is heterologous evidence transferred to the S. pombe protein. Native S. pombe data independently support a cytoplasmic pool, so the term is acceptable though the cited reference is mammalian. Reason: Cytoplasmic localization is supported by direct S. pombe data; the cited reference is mammalian and thus orthology-based. Supporting Evidence: PMID:1500423 cdc25 proteins are redistributed throughout the cytoplasm |
| GO:0010971 positive regulation of G2/M transition of mitotic cell cycle | IMP PMID:3955656 cdc25+ functions as an inducer in the mitotic control of fis... | ACCEPT | Summary: The original genetic identification of cdc25+ as a dosage-dependent mitotic inducer counteracting Wee1. Core process, foundational evidence. Reason: Foundational genetic evidence establishing Cdc25 as the positive regulator of mitotic entry. Supporting Evidence: PMID:3955656 cdc25+ functions to counteract the activity of the mitotic inhibitor wee1+ |
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Download this section (compressed HTML)Q: Beyond Cdc2-Tyr15, does Cdc25 have additional physiological substrates in S. pombe, or is Cdc2 its sole relevant target?
Q: How is the balance between the redundant Cdc25 and Pyp3 phosphatases regulated to set the precise timing of Tyr15 dephosphorylation?
Q: What is the relative contribution of nuclear exclusion versus direct catalytic inhibition to the 14-3-3-dependent checkpoint silencing of Cdc25?
Experiment: Phosphoproteomic and substrate-trapping (catalytically inactive Cys480Ser) assays to define the full in vivo substrate repertoire of Cdc25 beyond Cdc2-Tyr15.
Experiment: Quantitative live-cell imaging of endogenously tagged Cdc25 to measure how its nuclear/cytoplasmic concentration changes with cell size and across checkpoint activation, testing the threshold-concentration size-control model.
Experiment: Separation-of-function 14-3-3 binding-site mutants combined with forced nuclear or cytoplasmic targeting to dissect whether checkpoint inhibition of Cdc25 is driven primarily by relocalization or by intrinsic activity changes.
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